|
Title
|
|
|
|
Pasteurella multocida toxin stimulates mitogen-activated protein kinase via -dependent transactivation of the epidermal growth factor receptor
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| The dermatonecrotic toxin produced by Pasteurella multocida is one of the most potent mitogenic substances known for fibroblasts in vitro. Exposure to recombinant P. multocida toxin (rPMT) causes phospholipase C-mediated hydrolysis of inositol phospholipids, calcium mobilization, and activation of protein kinase C via a poorly characterized mechanism involving G(q/11) family heterotrimeric G proteins. To determine whether the regulation of G protein pathways contributes to the mitogenic effects of rPMT, we have examined the mechanism whereby rPMT stimulates the Erk mitogen-activated protein kinase cascade in cultured HEK-293 cells. Treatment with rPMT resulted in a dose and time-dependent increase in Erk 1/2 phosphorylation that paralleled its stimulation of inositol phospholipid hydrolysis. Both rPMT- and alpha-thrombin receptor- stimulated Erk phosphorylation were selectively blocked by cellular expression of two peptide inhibitors of G(q/11) signaling, the dominant negative mutant G protein-coupled receptor kinase, GRK2(K220R), and the G alpha(q) carboxyl-terminal peptide, G alpha(q)-(305359). Like alpha-thrombin receptor-mediated Erk activation, the effect of rPMT was insensitive to the protein kinase C inhibitor GF109203X, but was blocked by the epidermal growth factor receptor-specific tyrphostin, AG1478 and by dominant negative mutants of mSos1 and Ha-Ras, These data indicate that rPMT employs G(q/11) family heterotrimeric G proteins to induce Ras-dependent Erk activation via protein kinase C-independent "transactivation" of the epidermal growth factor receptor. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Journal of biological chemistry. - Baltimore, Md
| |
|
Publication
|
|
|
|
Baltimore, Md
:
2000
| |
|
ISSN
|
|
|
|
0021-9258
[print]
1083-351X
[online]
| |
|
DOI
|
|
|
|
10.1074/JBC.275.3.2239
| |
|
Volume/pages
|
|
|
|
275
:3
(2000)
, p. 2239-2245
| |
|
ISI
|
|
|
|
000084940000094
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (publisher's version - intranet only)
|
|
|
|
| |
|